There is growing evidence of a relationship between inflammation and psychiatric illness. In particular, the cytokine Interleukin-6 (IL-6) has been linked to stress-related disorders such as depression and anxiety. Here we discuss evidence from preclinical and clinical studies examining the role of IL-6 in mood disorders. We focus on the functional role of peripheral and central release of IL-6 on the development of stress susceptibility and depression-associated behavior. By examining the contribution of both peripheral and central IL-6 to manifestations of stress-related symptomatology, we hope to broaden the way the field thinks about diagnosing and treating mood disorders.